New black-boxed warning added to leflunomide prescribing information: warns of severe liver injury

In mid July, FDA released a drug safety communication to rheumatologists and family physicians warning them that the use of leflunomide (Arava, Sanofi-Aventis)-a drug to treat rheumatoid arthritis-has been linked to an increased risk of severe liver injury. This warning is also being included as second black-boxed warning in leflunomide’s prescribing information; the first, being a contraindication for use in pregnant women or women of childbearing potential who are not using reliable contraception.

This safety communication and new black-box warning come after an FDA review of adverse event reports between August 2002 and May 2009, in which FDA identified 49 cases of severe liver injury, including 14 cases of fatal liver failure and 36 requiring hospitalization. In addition, 5 patients receiving leflunomide required a liver transplant and 9 patients experienced “a life-threatening event.”

According to FDA officials, “To highlight the importance of appropriate patient selection and monitoring in reducing the risk of severe liver injury, the agency decided that specific recommendations to ensure safe use of leflunomide needed to be added to the Boxed Warning.”

The estimated duration of leflunomide treatment before the occurrence of severe liver injury ranged from 9 days to 6 years, with most developing severe liver injury within the first 6 to 12 months of treatment. Twenty-three reports described jaundice at the time of diagnosis, 11 reported coagulopathy and 5 reported encephalopathy. Other presenting symptoms in these cases included vomiting, rash and or itching, abdominal pain, and fever. The greatest risk for liver injury appeared to be in patients taking other drugs known to cause liver injury (including methotrexate, TNF-α blockers, hydroxychloroquine, acetaminophen, non-steroidal anti-inflammatory drugs, and statins), and patients with pre-existing liver disease (due to active or chronic hepatitis, and/or a history of alcohol abuse); however, 17 cases were reported in patients with normal liver enzymes prior to starting leflunomide.

As a result of the heightened awareness of this adverse effect, FDA is now recommending patients with pre-existing liver disease (acute or chronic infection with hepatitis B or C virus), or those with serum alanine transaminase (ALT) >2 times the upper limit of normal before initiating treatment should not be treated with leflunomide. Moreover, FDA is recommending ALT levels be monitored at least monthly for 3 months after starting leflunomide and at least quarterly thereafter.

In those experiencing a rise in their ALT >2 times the upper limit of normal while on leflunomide, FDA now suggests that the drug be stopped, cholestryamine washout begun (8 g 3 times daily for 11 days, with additional cholestryamine as needed to achieve a plasma level of 0.02 mg/L), and follow up liver function tests conducted at least weekly until normalization. This latter step is needed since without it cholestryamine washout, it may take up to 2 years to reach desired plasma levels.